This GO grant application aims to integrate the unique capabilities of nanotechnology and innovative optical instrumentation for broad applications in cancer surgery. The rationale for this surgical nanotechnology focus is that surgery currently cures approximately 45% of all patients with cancer, while chemotherapy and radiation therapy together only cure 5%. In fact, the single most important predictor of patient survival for almost all cancers is a complete surgical resection, by removing the primary tumor, draining lymph nodes and small adjacent satellite nodules. For human lung, breast, prostate, colon and pancreatic cancers, it has been shown that complete resection has a three to five fold improvement in survival compared to partial or incomplete resection. In the last 50 years, little progress has been made in improving intraoperative techniques, and currently over 40% of patients that undergo surgery still leave the operating room without a complete resection due to missed lesions. Thus, major opportunities exist to develop nanoparticle agents and intraoperative instrumentation that would allow a surgeon to visualize microscopic tumors, metastatic lymph nodes, and adjacent normal tissues during cancer surgery. This has the potential to make an enormous impact on a larger number of patients undergoing cancer surgery. Toward this goal, we propose here a translational and collaborative program involving 7 senior faculty investigators at three academic institutions (Emory, Georgia Tech, and the University of Pennsylvania) with broad expertise cutting across nanotechnology, biocomputing, molecular imaging, oncologic surgery, and medical oncology. Designed for accelerated development and clinical impact within two years, the overall project will focus on three major efforts: (1) optimization and standardization of a new class of biocompatible and nontoxic nanoparticle probes based on pegylated colloidal gold and surface-enhanced Raman scattering (SERS) (Nie and coworkers, Nature Biotech. 26, 83-90, 2008);(2) systems integration and implementation for intraoperative cancer detection and visualization, especially by using handheld "point-and-detect" devices;and (3) translational experiments demonstrating nanotechnology surgical applications in animal models of aggressive tumors such as lung cancer, pancreatic cancer, and metastatic breast cancer. The proposed research could ultimately make an impact in reducing the currently high mortality rates of these and other human malignancies. Once developed, the nanoparticle agents and miniaturized optical devices can also be used for robotic and minimally invasive surgery, such as endoscopic and laparoscopic procedures to detect and resect solid tumors. This project is expected to yield several practical outcomes including standardized gold nanoparticles for multiplexed cancer detection, new spectroscopic and imaging instruments for cancer detection, software and databases for multiplexed spectral imaging and tissue identification, as well as new employment opportunities. Public Health Relevance: This grant application aims to develop new and innovative technologies for applications in cancer surgery. The main goals are to help the surgeon to delineate tumor margins, to identify residual tumor cells and micrometastases, and to determine if the tumor has been completely removed. This work is expected to ultimately make an impact in reducing the currently high mortality rates of lung, pancreatic and metastatic breast cancers.